Sustained release excipient and tablet formulation

ABSTRACT

A slow release pharmaceutical excipient of an inert diluent and a hydrodrophilic material including xanthan gum and a galactomannan gum capable of cross-linking the xanthan gum in the presence of aqueous solutions.

This application is a continuation-in-part of U.S. application Ser. No.246,368, filed Sep. 19, 1988, now U.S. Pat. No. 4,994,276.

FIELD OF THE INVENTION

The present invention relates to a sustained release pharmaceuticalexcipient product which can be blended with a wide range oftherapeutically active medicaments and tableted.

BACKGROUND OF THE INVENTION

Many attempts have been made in the pharmaceutical art to provide amethod by which therapeutically active medicaments can be directlytableted or mixed with a direct compression vehicle and thereafterdirectly tableted.

Very few therapeutically active medicaments can be directly tableted dueto unacceptable flow characteristics and compressibility factors of thecrystalline or powdered medicament, and also due to the small amounts ofmedicament needed to provide the desired effect. Therefore, it is acommon practice to use an inert ingredient, i.e., excipients, diluents,fillers, binders and the like, such that the combination of the samewith the medicament provides a material which can be directly compressedinto tablets. In order to provide a directly compressible product, theseexcipients must have certain physical properties, including flowability,sufficient particle size distribution, binding ability, acceptable bulkand tap densities, and acceptable dissolution properties in order torelease the medicament upon oral administration.

U.S. Pat. No. 3,639,169 (Broeg et al.) discloses one such directcompression vehicle for a therapeutically active medicament whichconsists of an insoluble or soluble diluent such as lactose dispersed ina matrix of a hydrophilic hydratable high polymer such as hydrophilicpolysaccharides, hydrocolloids or proteinaceous materials. The polymer,diluent and water are mixed and the resulting dispersion is dried,forming a film. The cooled film is fragmented, ground to the desiredparticle size and then blended with a desired medicament.

In another method disclosed in U.S. Pat. No. 3,079,303 (Raff et al.), agranular excipient for making tablets is prepared by spray drying aslurry of 50%-98% filler, 1%-50% disintegrant, and 1%-50% binder. Amedicament is then added to the excipient and the finished product istableted.

It has become desirable to provide pharmaceutical formulations whichutilize slow release profiles, an objective not contemplated in Broeg etal., Raff et al. or other similar prior art. The advantages of slowrelease products are well known in the pharmaceutical field and includethe ability to maintain a desired blood level over a longer period oftime while increasing patient compliance by reducing the number ofadministrations necessary to achieve the same.

Slow release excipients have been developed which attain their goals bya wide variety of methods. For instance, U.S. Pat. No. 3,629,393(Nakamoto) utilizes a three-component system to provide slow releasetablets in which granules of an active ingredient with a hydrophobicsalt of a fatty acid and a polymer are combined with granules of ahydrocolloid and a carrier and granules of a carrier and an active or abuffering agent and then directly compressed into tablets. U.S. Pat. No.3,728,445 (Bardani) discloses slow release tablets formed by mixing anactive ingredient with a solid sugar excipient, granulating the same bymoistening with a cellulose acetate phthalate solution, evaporating thesolvent, recovering the granules and compressing under high pressure.These disclosures concentrate their attention to the type andcombination of polymers and/or gums used, and processes for mixing thesame, and therefore have not provided a directly compressible form ofgums/polymers and adjuvants which can be used for a wide range ofmedicaments.

Other slow release excipients are disclosed in the prior art which aredirected to particular therapeutically active medicaments.

In one such disclosure, U.S. Pat. No, 3,456,049 (Hotko et al.), a slowrelease benzothiadiazine diuretic tablets are prepared by mixing a fattysubstance such as hydrogenated vegetable oil, alginic acid, agranulating liquid, a potassium salt and the benzothiadiazine. The wetmass is screened, dried, and then compressed into tablets. Similarly,U.S. Pat. No. 4,692,337 (Ukigaya et al.) provides a slow releaseexcipient for theophylline which utilizes 5-200 parts of ethyl cellulosefor each 100 parts theophylline, and optionally contains a filler suchas lactose or a lubricant. The ingredients are mixed and compressionmolded into tablets. In yet another example, U.S. Pat. No. 4,308,251(Dunn et al.), a sustained release aspirin formulation in which 0.8-1.6percent of a release controlling agent (cellulose acetate phthalate) and1.0-7.5 percent of an erosion-promoting agent (corn starch) by weightper tablet. A wet granular mass is formed, dried, reduced in particlesize and compressed into tablets.

More recently, a great deal of attention in the pharmaceutical field hasturned to the use of various hydrocolloid materials such ashydroxypropylmethyl cellulose in providing a slow release matrix for avariety of medicaments.

For example, U.S. Pat. No. 4,389.393 (Schor et al.) describes a slowrelease carrier base material of one or more hydroxypropylmethylcelluloses and up to 30% by weight of a mixture of methylcellulose,sodium carboxymethylcellulose and/or cellulose ether which can be mixedwith a medicament and other needed ingredients such as binders,lubricants, etc. and then tableted. At least one of thehydroxypropylmethyl celluloses must have a methoxy content of 16%-24% byweight, a hydroxypropyl content of 4%-32% by weight, and a numberaverage molecular weight of at least 50,000. The carrier baseconstitutes less than about one third of the weight of the solid unitdosage form.

It is acknowledged in Schor et al. that in order to make tablets usingthis carrier base, other ingredients which are conventional in tabletmaking must necessarily be included, such as binders, fillers,disintegrating agents and the like. Only the completed mixture, whichincludes these additional ingredients, possess sufficient properties toproduce tablets having the necessary hardness and low level offriability. Thus, the carrier base of the Schor et al. disclosure is notdirected to the tableting aspects.

U S. Pat. No. 4,704,285 (Alderman) discloses solid slow release tabletscontaining 5%-90% hydroxypropyl cellulose ether, 5%-75% of an optionaladditional hydrophilic colloid such as hydroxypropylmethyl cellulose, aneffective amount of an active medicament, and optional binders,lubricants, glidants, fillers, etc. The hydroxypropyl cellulose ether isin the form of a finely sized powder and provides a longer releasepattern than identical compositions having coarser particles. However,Alderman acknowledges the necessity of the additional excipients inorder to form an acceptable solid tablet, (i.e. fillers, binders,lubricants and glidants). In preferred embodiments, these excipientscomprise from 63.5%-94% of the tablet.

The carrier bases which provide the slow release profiles in thesedisclosures can only be compressed into a tablet or a solid dosage formwith the aid of other conventional tableting adjuvants such as bindersand the like, and therefore contribute only to the slow release aspectof the final solid unit dosage form and not to the tableting aspects. Inother words, in each of these disclosures it is necessary for to firstdetermine the physical properties of the active medicament to betableted and thereafter proceed through a series of trial and errorexperiments in order to determine the optimal amount of gums/polymersand other adjuvants to produce the right formulation which is freeflowing and which can be compressed to a slow release solid dosage unit.This procedure is time intensive and costly.

Similarly, slow release excipients disclosed to date which incorporatevirtually any synthetic polymer such as hydroxypropylmethylcellulose,methyl cellulose, polyvinylpyrollidone, and any natural gum such asacacia tragacanth, alginates, chitosan, xanthan, pectin and others todate have been mainly directed to the slow release aspect and do notsatisfactorily address the tableting aspect. This is because thesematerials are not available in the necessary physical form that isessential for forming a solid unit dosage form.

The failure of slow release excipients such of the above to be regardedas to their tableting properties is due, for instance, to theirnecessarily very fine particle size, which property does not lend itselfwell to flowability. Also, hydroxypropylmethyl cellulose polymers andthe like are not particularly good binding agents, a problem which isamplified when other poorly binding excipients or medicaments areincluded in a formulation. Thus, at higher percentages of such polymersin the final mixture, it becomes difficult if not impossible to providea good flowing tablet formulation for direct compression without the useof further excipients, and experimentation.

The tableting aspect has been addressed, albeit unsatisfactorily, inU.S. Pat. No. 4,590,062 (Jang). Jang discloses a dry direct compressedslow release tablet containing from 0.01 to 95 parts by weight of anactive ingredient combined with a matrix blend of 1-96 parts of ahydrophobic carbohydrate polymer and 4-99 parts of a wax, and a fattyacid material or neutral lipid. The tablets can be made by dry blendingthe active ingredient with the matrix blend and compressing. However,while this combination of ingredients can provide a directlycompressible tablet, the formulator is still required to perform a greatdeal of experimentation to provide the correct release profile for thechosen medicament, given the wide range of wax (used for its binding andcompacting properties) which can be included.

It is therefore an object of the present invention to provide afree-flowing directly compressible slow release excipient which can beused for a wide variety of therapeutically active medicaments.

It is another object of the present invention to provide an excipientwhich can be prepared by wet granulation to form controlled releasetablets.

It is a further object of the present invention to provide an excipienthaving the properties set forth above which can be used with bothrelatively soluble and relatively insoluble therapeutically activemedicaments.

It is a further object of the present invention to provide afree-flowing directly compressible slow release excipient which isrelatively inexpensive to manufacture due to the lack of coatings andexpensive equipment.

SUMMARY OF THE INVENTION

In accordance with the above-mentioned objectives, the present inventionprovides a slow release pharmaceutical excipient comprising from about20 to about 70 percent or more by weight of a hydrophilic materialcomprising a heteropolysaccharide and a polysaccharide material capableof cross-linking the heteropolysaccharide in the presence of aqueoussolutions, and from about 30 to about 80 percent by weight of an inertpharmaceutical filler. This excipient can be mixed with a wide range oftherapeutically active medicaments and then directly compressed intosolid dosage forms such as tablets. The tablets thus formed slowlyrelease the medicament when ingested and exposed to gastric fluids. Byvarying the amount of excipient relative to the medicament, a slowrelease profile can be attained.

The heteropolysaccharide comprises from about 20 to about 80 percent andthe polysaccharide material comprises from about 80 to about 20 percentby weight of the hydrophilic matrix. Preferably, the ratio ofheteropolysaccharide to polysaccharide material is about 1:1.

In preferred embodiments, the heteropolysaccharide comprises xanthan gumor a derivative thereof.

In another preferred embodiment, the polysaccharide material comprisesone or more galactomannans. Most preferably, the polysaccharide materialcomprises locust bean gum.

In yet another preferred embodiment, the inert pharmaceutical fillercomprises lactose, dextrose, sucrose, sorbitol, xylitol, fructose ormixtures thereof.

The present invention also provides a slow release granulation for useas a directly compressible pharmaceutical excipient, comprising aheteropolysaccharide or a gum having similar properties and apolysaccharide material capable of cross-linking theheteropolysaccharide in the presence of water, the ratio of theheteropolysaccharide to the polysaccharide material being from about 1:1to about 4:1.

The present invention also provides a slow release tablet for oraladministration comprising (I) a hydrophillic material comprising (a) aheteropolysaccharide; or (b) a heteropolysaccharide and a cross-linkingagent capable of cross-linking said heteropolysaccharide; or (c) amixture of (a), (b) and a polysaccharide gum; and (II) an inertpharmaceutical filler comprising up to about 80 percent by weight of thetablet; and (III) an effective amount of a therapeutically activeingredient.

In addition, the present invention provides a method for providing auniversal tableting excipient for controlled release of therapeuticallyactive medicaments having varied solubilities in water, comprisingdetermining the solubility of a therapeutically active medicament whichis to be tableted; mixing an effective amount of said therapeuticallyactive medicament with a premanufactured granulated slow releaseexcipient comprising from about 20 to about 70 percent by weight of ahydrophilic material comprising a heteropolysaccharide and apolysaccharide capable of cross-linking said heteropolysaccharide in thepresence of aqueous solutions, and up to 80 percent by weight of aninert pharmaceutical filler; providing a final mixed product having aratio of said therapeutically active medicament to said hydrophilicmaterial of about 1:3-7 depending upon the relative solubility of themedicament, amount of medicament needed (dose), the desired total weightof the tablet, the compression force used, etc.; and thereafter directlycompressing the resulting blend to form a tablet. Generally, the moresoluble the medicament, the greater the amount of hydrophilic materialneeded to produce a slow release of the medicament.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graphical representation of the dissolution curves providedby Examples 3-6;

FIG. 2 is a graphical representation of the dissolution curves providedby Examples 16-19;

FIG. 3 is a graphical representation of the dissolution curves providedby Examples 18,20 and 28;

FIG. 4 is a graphical representation of the dissolution curve providedby Example 18 as compared to Comparative Example C;

FIG. 5 is a graphical representation of the dissolution curve providedby Examples 29-31 (in different pH's); and

FIG. 6 is a graphical representation of the viscosities of Examples32-36.

FIG. 7 is a graphical representation of the dissolution curves providedby Examples 41-43;

FIG. 8 is a graphical representation of the dissolution curves providedby Examples 44-46;

FIG. 9 is a graphical representation of the dissolution curves providedby Examples 47-50;

FIG. 10 is a graphical representation of the dissolution curves providedby Examples 51-53;

FIG. 11 is a graphical representation of the dissolution curves providedby Example 54 and Calan® SR;

FIG. 12 is a graphical representation of the dissolution curves providedby Example 55 and Inderal® LA;

FIG. 13 is a graphical representation of the dissolution curves providedby Example 56 and Chlortrimeton®;

FIG. 14 is a graphical representation of the dissolution curves providedby Example 57 and Acutrim®; and

FIG. 15 is a graphical representation of the bioavailability of Example57 as compared to Acutrim®.

DETAILED DESCRIPTION

The excipients of the present invention have been preoptimized byproviding an excipient product which may be mixed with a wide range ofmedicaments and directly compressed into solid dosage forms, without theaid of the usual pharmaceutical dry or wet binders, fillers,disintegrants, glidants etc. which must be added in prior artcompositions to obtain an acceptable solid dosage form. Thus, theexcipients of the present invention substantially overcome the need forconducting further experimentation needed to optimize releasecharacteristics and tableting properties for a particulartherapeutically active medicament.

In other words, the present invention provides a novel slow releaseexcipient product which contains a combination of ingredients inpreselected proportions to each other which provides a desired slowrelease profile for a wide variety of drugs. Thus, once the excipientproduct is admixed with an active medicament (and optional lubricant) ina ratio to the hydrophilic matrix in accordance with the presentinvention, the resulting mixture may be directly compressed into soliddosage forms.

Xanthan gum, the preferred heteropolysaccharide, is produced bymicroorganisms, for instance, by fermentation with the organismxanthomonas compestris. Most preferred is xanthan gum which is a highmolecular weight (>10⁶) heteropolysaccharide. Xanthan gum containsD-glucose, D-mannose, D-glucuronate in the molar ratio of 2.8:2.0:2.0,and is partially acetylated with about 4.7% acetyl. Xanthan gum alsoincludes about 3% pyruvate, which is attached to a single unitD-glucopyromosyl side chain as a ketal. It dissolves in hot or coldwater and the viscosity of aqueous solutions of xanthan gum is onlyslightly affected by changes in the pH of a solution between 1 and 11.

Other preferred heteropolysaccharides include derivatives of xanthangum, such as deacylated xanthan gum, the carboxymethyl ether, and thepropylene glycol ester.

The polysaccharide materials used in the present invention which arecapable of cross-linking with the heteropolysaccharide include thegalactomannans, i.e., polysaccharides which are composed solely ofmannose and galactose. A possible mechanism for the interaction betweenthe galactomannan and the heteropolysaccharide involves the interactionbetween the helical regions of the heteropolysaccharide and theunsubstituted mannose regions of the galactomannan. Galactomannans whichhave higher proportions of unsubstituted mannose regions have been foundto achieve more interaction with the heteropolysaccharide. Hence, locustbean gum, which has a higher ratio of mannose to galactose, isespecially preferred as compared to other galactomannans such as guarand hydroxypropyl guar.

Other polysaccharide gums may also be added to the hydrophilic materialin addition to the above-mentioned ingredients. These additionalingredients comprise other polysaccharide gums which may or may notcross-link with the heteropolysaccharides such as the alginates,tragacanth, acacia, karaya, agar, pectins, carrageenan,hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, polyvinyl pyrrolidone, mixtures thereof, and the like.

Two steps which are generally required for gelation are the fasthydration of the macromolecules which comprise the hydrophilic materialand thereafter the association of the molecules to form gels. Thus, twoimportant properties of a hydrophilic gel matrix which are needed forapplication in a slow release system are the fast hydration of thesystem and a matrix having a high gel strength. These two importantproperties which are necessary to achieve a slow release hydrophilicmatrix are maximized in the present invention by the particularcombination of materials. In particular, heteropolysaccharides such asxanthan gum have excellent water wicking properties which provide fasthydration. On the other hand, the combination of xanthan gum withpolysaccharides materials and the like which are capable ofcross-linking the rigid helical ordered structure of the xanthan gum(i.e. with unsubstituted mannose regions in galactomannans) thereby actsynergistically to provide a higher than expected viscosity (i.e., highgel strength) of the matrix.

Certain other polysaccharide gums, including alginic acid derivatives,hydrocolloids, etc. also are believed to act synergistically withxanthan gum to produce matrices having high gel strength. Thecombination of xanthan gum with locust bean gum with or without theother polysaccharide gums is especially preferred. However, thecombination of any polysaccharide gums known to produce a synergisticeffect when exposed to aqueous solutions may be used in accordance withthe present invention. By synergistic effect it is meant that thecombination of two or more polysaccharide gums produce a higherviscosity and/or faster hydration than that which would be expected byeither of the gums alone. One example of a combination of polysaccharidegums which has been reported to exhibit such synergism in food productsis kappa carrageenan and a galactomannan such as guar gum and/or locustbean gum. Additionally, the combination of propylene glycol alginate andsodium carboxymethylcellulose has also been reported to exhibit asynergistic effect as a stabilizer in fruit juices in U.S. Pat. No.4,433,000. This list is not meant to be exclusive, and many othersynergistic combinations will be readily apparent to those skilled inthe art.

Mixtures of xanthan gum and locust bean gum in a ratio from about 20:1to about 1:10 are disclosed in U.S. Pat. No. 3,726,690 (Schuppner) asbeing useful to minimize serum separation in amounts of 0.2%-0.6% byweight of acidified food products. In addition, mixtures of xanthangum/locust bean gum are commercially available as Lygomme H96 from Satiaand are recommended for uses such as syrup thickening, suspension ofactive components and emulsion stabilization.

In the present invention it has been discovered that the slow releaseproperties of the tablets are optimized when the ratio of xanthan gum topolysaccharide material (i.e., locust bean gum, etc.) is about 1:1,although xanthan gum in an amount of from about 20 to about 80 percentor more by weight of the hydrophilic material provides an acceptableslow release product.

Upon oral ingestion and contact with gastric fluid, the slow releasetablets prepared according to the present invention swell and gel toform a hydrophilic gel matrix from which the drug is released. Theswelling of the matrix causes a reduction in the bulk density of thetablet and provides the buoyancy necessary to allow the gel mass tofloat on the stomach contents to provide a slow delivery of themedicament. The matrix, the size of which is dependent upon the size ofthe original tablet, can swell considerably and become obstructed nearthe opening to the pylorus. Since the medicament is dispersed throughoutthe tablet (and consequently throughout the gel matrix), a constantamount of drug can be released per unit time in vivo by dispersion orerosion of the outer portions of the matrix. This phenomenon is commonlyreferred to as a zero order release profile or zero order kinetics. Theprocess continues, with the matrix remaining buoyant in the stomach,until substantially all of the medicament is released. The chemistry ofcertain of the ingredients comprising the excipients of the presentinvention such as xanthan gum is such that the excipients are consideredto be self-buffering agents which are substantially insensitive to thesolubility of the medicament and likewise insensitive to the pH changesalong the length of the gastrointestinal tract. Moreover, the chemistryof the ingredients comprising the excipients of the present invention isbelieved to be similar to certain known muco adhesive substances such aspolycarbophil. Muco adhesive properties are desirable for buccaldelivery systems. Thus, it may be possible that the gel system couldpotentially loosely interact with the mucin in the gastrointestinaltract and thereby provide another mode by which a constant rate ofdelivery of the medicament is achieved. The above hypothesis is includedfor discussion purposes only and is not intended to limit the scope ofthe present invention.

These two phenomenons, i.e., buoyancy of the gel matrix and themucoadhesive properties discussed above, are possible mechanisms bywhich the gel matrix of the present invention could interact with themucin and fluids of the gastrointestinal tract and provide a constantrate of delivery of the medicament. Other mechanisms are possible andtherefore this hypothesis is not meant to limit the scope of the presentinvention.

Any generally accepted soluble or insoluble inert pharmaceutical filler(diluent) material can be used, including sucrose, dextrose, lactose,microcrystalline cellulose, xylitol, fructose, sorbitol, mixturesthereof and the like. However, it is preferred that a solublepharmaceutical filler such as lactose, dextrose, sucrose, or mixturesthereof be used.

An effective amount of any generally accepted pharmaceutical lubricant,including the calcium or magnesium soaps may be added to theabove-mentioned ingredients of the excipient at the time the medicamentis added, or in any event prior to compression into a solid dosage form.Most preferred is magnesium stearate in an amount of about 0.5 %-3% byweight of the solid dosage form.

The combination of the hydrophilic material (i.e., a mixture of xanthangum and locust bean gum) with the inert diluent provides a ready to useproduct in which a formulator need only blend the desired activemedicament and an optional lubricant with the excipient and thencompress the mixture to form slow release tablets. The excipient maycomprise a physical admix of the gums along with a soluble excipientsuch as compressible sucrose, lactose or dextrose, although it ispreferred to granulate or agglomerate the gums with plain (i.e,crystalline) sucrose, lactose, dextrose, etc. to form an excipient. Thegranulate form has certain advantages including the fact that it can beoptimized for flow and compressibility; it can be tableted, formulatedin a capsule, extruded and spheronized with an active medicament to formpellets, etc.

The pharmaceutical excipients prepared in accordance with the presentinvention are preferably subjected to wet granulation before themedicament is added, although the ingredients of the present excipientcan be held together by any agglomeration technique to yield anacceptable excipient product. In this technique, the desired amounts ofthe heteropolysaccharide, the polysaccharide material, and the inertfiller are mixed together and thereafter a moistening agent such aswater, propylene glycol, glycerol, alcohol or the like is added toprepare a moistened mass. Next, the moistened mass is dryed. The driedmass is then milled with conventional equipment into granules.Thereafter, the excipient product is ready to use.

The excipient is free-flowing and directly compressible. Accordingly,the excipient may be mixed in the desired proportion with atherapeutically active medicament and optional lubricant (drygranulation). Alternatively, all or part of the excipient may besubjected to a wet granulation with the active ingredient and thereaftertableted. The complete mixture, in an amount sufficient to make auniform batch of tablets, is then subjected to tableting in aconventional production scale tableting machine at normal compressionpressures, i.e. about 2000-16000 lbs/sq. in. However, the mixture shouldnot be compressed to such a degree that there is subsequent difficultyin its hydration when exposed to gastric fluid.

One of the limitations of direct compression as a method of tabletmanufacture is the size of the tablet. If the amount of active is high apharmaceutical formulator may choose to wet granulate the active withother excipients to attain a decent size tablet with the right compactstrength. Usually the amount of filler/binder or excipients needed inwet granulation is less than that in direct compression since theprocess of wet granulation contributes to some extent toward the desiredphysical properties of a tableting mix.

The average tablet size for round tablets is preferably about 500 mg to750 mg and for capsule-shaped tablets about 750 mg to 1000 mg.

The average particle size of the granulated excipient of the presentinvention ranges from about 50 microns to about 400 microns andpreferably from about 185 microns to about 265 microns. The particlesize of the granulation is not narrowly critical, the importantparameter being that the average particle size of the granules, mustpermit the formation of a directly compressible excipient which formspharmaceutically acceptable tablets. The desired tap and bulk densitiesof the granulation of the present invention are normally between fromabout 0.3 to about 0.8 g/ml, with an average density of from about 0.5to about 0.7 g/ml. For best results, the tablets formed from thegranulations of the present invention are from about 6 to about 8 kghardness. The average flow of the granulations prepared in accordancewith the present invention are from about 25 to about 40 g/sec.

The ratio of medicament to the hydrophilic material is based in partupon the relatively solubility of the medicament and the desired rate ofrelease. For instance, the ratio of medicament to hydrophilic materialcan be adjusted to yield a product wherein 50 percent of the medicamentwill dissolve in distilled water within about 3.5-5 hours if a 6-8 hourdosing preparation is desired. This is accomplished by providing a ratioof medicament to hydrophilic material of about 1:3-7 for a wide range ofmedicaments of varying solubilities. However, it would be obvious to oneskilled in the art that by varying this proportion and/or the totalweight of the tablet, etc., one can achieve different slow releaseprofiles, and may extend the dissolution of some medicaments to about 24hours. If the medicament is relatively insoluble, the ratio ofmedicament to hydrophilic material tends to be smaller, while if themedicament is relatively soluble, the ratio tends to be toward thegreater end. By "relatively insoluble", it is meant that the medicamentexhibits a solubility which is defined in the United States Pharmacopeia(USP) XXI, page 7 as requiring about 10-30 parts solvent for 1 partsolute (described therein as "soluble"). An example of a medicamentwhich is considered relatively insoluble for the purposes of the presentinvention is propranol hydrochloride, which has a solubility of about 1gram in 20ml of water or alcohol. By "relatively soluble", it is meantthat the medicament exhibits a solubility which is defined in the USPXXI, page 7 as requiring from about 1-10 parts solvent per 1 part solute(described therein as "freely soluble). Examples of medicaments whichare considered relatively soluble for the purposes of the presentinvention include chlorpheniramine maleate, which has a solubility of 1g in 4 ml of water or 10 ml of alcohol, and verapamil HCl. Examples ofother medicaments which have solubilities falling within theseapproximate parameters may be determined from any number of sources suchas the Solubility Reference Table found in the USP XXI, pages 1484-9.

The excipient product of the present invention is also contemplated foruse in conjunction with insoluble medicaments. By "insoluble", it ismeant that the medicament exhibits a solubility which is defined in theUSP XXI, page 7 as requiring from about 30-1000 parts solvent per 1 partsolute (described) therein as "sparingly soluble" and "slightlysoluble"). In such circumstances, the excipient product will be actingto control the release of the medicament rather than necessarily slowingits release. An example of such an insoluble medicament is theophylline.

As previously mentioned, the excipient product of the present inventioncan be used in conjunction with a wide range of medicaments. Sinceprecise dosing is not very critical in medicaments having a widetherapeutic window, the present invention is especially well-suited forthe same. The therapeutic window is commonly defined as the differencebetween the minimum effective blood concentration and the maximumeffective blood concentration and the toxic concentration of themedicament.

Variables which may affect the release rate and compressibility oftablets prepared with the excipient of the present invention are:

a) Drug to polymer ratio;

b) Method of incorporation of excipient (Method of granulation);

c) Amount of gum blend; and

d) Composition of gum mix.

Examples of such medicaments which can be used in accordance with thepresent invention include analgesics, antihistamines, decongestants,laxatives, antacids, vitamins, anti-infectives, anti-inflammatories,antibiotics, vasoconstrictors, vasodilators, psychotropics, stimulantsincluding appetite suppressants, diuretics, anti-asthmatics, diuretics,anti-spasmodics, antidiarrheals, expectorants, mucolytics, coughsuppressants, hypnotics, psychotropics, sedatives and others.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1 Preparation of Excipient

A slow release excipient according to the present invention is preparedas follows. First, 600 g of sucrose and 300 g of a mixture of xanthangum and locust bean gum in approximately a 1:1 ratio, all in powder formhaving an average particle size of less than about 50 microns, areblended for two minutes in a granulator (i.e., a high speed mixer havinga combination chopper/impeller). About 125 ml of water is added to themixture until there is a sharp rise in the power consumed (about 2-3minutes). The mixed product, which is now in the form of granules, isremoved from the granulator and dried in a convection air-oven for 24hours at a temperature of about 40° C.-60° C. The dried granulation isthen passed through a 20 mesh screen. The product is now ready to beused as a slow release excipient which is suitable for directcompression with any active medicament to form a slow release tablet.

EXAMPLE 2 Dry Granulation

Slow release tablets according to the present invention are prepared asfollows. The excipient of Example 1 is first blended withchlorpheniramine maleate for 10 minutes in a V-blender. Magnesiumstearate is then added as a lubricant and the mixture is blended for anadditional 5 minutes. The final composition of the mixture is about87.5% of the excipient of Example 1, 12% chlorpheniramine maleate, and0.5% magnesium stearate by weight.

The mixture is then compressed on a Stokes RB-2 rotary tablet press withsixteen stations, the target weight of the tablets being 100 mg and thecrushing strength about 6-8 kgs.

EXAMPLE 3-15 Chlorpheniramine

Slow release chlorpheniramine maleate tablets are prepared according tothe procedures set forth in Examples 1 and 2, except that the excipientformulation is varied such that the amount of hydrophilic material (forpurposes of the present examples referred to as "gums") relative to thetotal amount of excipient is varied from 20%-50%. In each of Examples3-15, the gums are xanthan gum/locust bean gum in approximately a 1:1ratio. In Examples 3-8, the inert diluent is dextrose. In Examples 9-11,the inert diluent is sucrose. The inert diluent in Examples 12 and 13 islactose, while in Examples 14 and 15 the inert diluent is a 50/50mixture of lactose and dextrose. In each of Examples 3-15, the totalweight of the tablets is 100 mg. The amount of chlorpheniramine maleatein each of these Examples is 12 mg except for Example 8, in which only 8mg of the drug were incorporated.

In addition, comparative examples A and B are prepared. Example A isprovided with an excipient comprising 30% hydroxypropylmethyl cellulose(grade K15M, available from Dow Chemical) and 70% dextrose. Example B asprovided with an excipient comprising 30% hydroxypropylmethyl cellulose(grade K4M, available from Dow Chemical) and 70% dextrose. ComparativeExamples A and B include 12 mg chlorpheniramine maleate in 100 mgtablets.

The granules are tested for tap and bulk density. In addition, theaverage particle size of the granulations is determined. The results areset forth in Table 1. Thereafter, the tablets produced in Examples 3-15and comparative examples A and B are tested for dissolution in distilledwater in an automated USP dissolution apparatus. The data is representedas the percentage of chlorpheniramine maleate released versus time. Theresults are provided in Table 2.

As can be seen from the dissolution data provided in Table 2, Examples4-6, 11, 13 and 15 provide dissolution profiles whereby 50% of the drugdissolves in from about 3.5-5.5 hours. Examples 3, 8, 9, 10 and 14, onthe other hand, produced dissolution profiles in which 50% of the drugdissolved within 3 hours. The difference in dissolution rates is relatedto the ratio of drug to the gums (in addition to other criteria, such asthe total amount of gums in the tablet, etc.). In particular,dissolution of 50% of the drug in 3.5-5.5 hours is accomplished withdrug/gums ratios of 1:2.2-3.8, while the shorter dissolution times areaccomplished with a drug/gums ratios of 1:1.5-2.2. The slight overlap isdue to the choice of inert diluents. Comparative Examples A and B (whichincluded only a hydrocolloid as the gum and which did not include theheteropolysaccharide and cross-linking agent of the present invention)only provide a T₅₀ of 1-1.5 hours when utilizing comparable amounts ofgum.

FIG. 1 is a graphical representation of the dissolution curves ofExamples 3-6. As can be seen from the graph, the dissolution curves ofExamples 4-6 in which the hydrophilic material (i.e., the gums) comprisefrom 30%-50% of the tablet, are similar, while Example 3 (20% gum) showsa much faster dissolution rate. The dissolution curves obtained whenother diluents are used and the percentage of gums in the tablet changedalso reflected this result.

                                      TABLE 1                                     __________________________________________________________________________    Chlorpheniramine Maleate Tablets (100 mg)                                                                Average                                                                       Particle                                                     Amt % Gums in                                                                           Ratio of                                                                             size                                               Example                                                                            Diluent                                                                            Drug                                                                              Excipient                                                                           Drug/Gums                                                                            (microns)                                                                           D.sub.B.sup.2                                                                    D.sub.T.sup.3                             __________________________________________________________________________    3    Dextrose                                                                           12 mg                                                                             20%   1:1.5  239   0.61                                                                             0.72                                      4    Dextrose                                                                           12 mg                                                                             30%   1:2.2  217   0.64                                                                             0.76                                      5    Dextrose                                                                           12 mg                                                                             40%   1:3    187   0.64                                                                             0.78                                      6    Dextrose                                                                           12 mg                                                                             50%   1:3.6  202   0.57                                                                             0.70                                      7    Dextrose                                                                           12 mg                                                                             33%   1:2.4  206   0.60                                                                             0.72                                      8    Dextrose                                                                            8 mg                                                                             33%   1:3.8  206   0.60                                                                             0.72                                      9    Sucrose                                                                            12 mg                                                                             20%   1:1.5  265   0.59                                                                             0.70                                      10   Sucrose                                                                            12 mg                                                                             30%   1:2.2  252   0.58                                                                             0.71                                      11   Sucrose                                                                            12 mg                                                                             40%   1:3    209   0.59                                                                             0.75                                      12   Lactose                                                                            12 mg                                                                             30%   1:2.2  178   0.65                                                                             0.81                                      13   Lactose                                                                            12 mg                                                                             40%   1:3    185   0.62                                                                             0.76                                      14   L/D.sup.1                                                                          12 mg                                                                             30%   1:2.2  227   0.57                                                                             0.69                                      15   L/D.sup.1                                                                          12 mg                                                                             40%   1:3    221   0.59                                                                             0.70                                      A    Dextrose                                                                           12 mg                                                                             30%   1:2.2  226   0.43                                                                             0.56                                      B    Dextrose                                                                           12 mg                                                                             30%   1:2.2  233   0.46                                                                             0.58                                      __________________________________________________________________________     .sup.1 denotes a 50/50 mixture of lactose and dextrose                        .sup.2 denotes bulk density                                                   .sup.3 denotes tap density                                               

                  TABLE 2                                                         ______________________________________                                        Chlorpheniramine Maleate Tablets (100 mg)                                     Dissolution Data (Distilled Water)                                            Example  2 hr     4 hr   8 hr   T.sub.50.sup.4                                                                      T.sub.90.sup.5                          ______________________________________                                        3        63.63    85.69  100    1-1.5 3.5-4                                   4        34.37    51.69  82.61  3.5-4 9-9.5                                   5        27.05    43.05  72.74  4.5-5 10.5-11                                 6        26.68    40.85  69.16  5-5.5 10.5-11                                 7        35.31    52.84  75.43  3-4   10-11                                   8        39.29    61.64  92.21  2-3   7-8                                     9        55.87    76.61  96.96  1.5-2 6-6.5                                   10       40.15    59.32  84.59  2.5-3 8.5-9                                   11       26.18    42.52  68.10  4-4.5 11-11.5                                 12       41.08    54.56  79.03  3-3.5 9-9.5                                   13       30.68    45.74  73.26  4.5-5 10-10.5                                 14       43.77    68.11  100    2-2.5 6-6.5                                   15       27.17    42.10  70.34  5.5   10.5-11                                 A        59.55    82.44  95.44  1-1.5 5.5-6                                   B        69.44    95.22  100    1-1.5 2.5-3                                   ______________________________________                                         .sup.4 denotes the time needed for 50% of the medicament to be released.      .sup.5 denotes the time needed for 90% of the medicament to be released. 

EXAMPLES 16-19 Propranol

Slow release propranolol hydrochloride tablets are prepared according tothe procedures set forth in Examples 1 and 2, except that the excipientformulation is varied such that the amount of hydrophilic material(referred to as "gums") relative to the total amount of excipient isvaried between 40% and 50% and the total weight of the tablets variedfrom 200-350 mg. In each of Examples 16-19, the gums are xanthangum/locust bean gum in approximately a 1:1 ratio and the amount ofpropranol hydrochloride is 20 mg. In Example 16, the inert diluent islactose. In Example 17, the inert diluent is a 50/50 mixture of lactoseand dextrose. Finally, in Examples 18 and 19, the inert diluent isdextrose and sucrose, respectively.

The granulations which are produced are tested for tap and bulk density.In addition, the average particle size of the granulations aredetermined. The results are set forth in Table 3. Thereafter, thetablets produced are tested for dissolution in distilled water in a USPdissolution apparatus which is automated. The data is represented as thepercentage of propranol hydrochloride released versus time. The resultsare provided in Table 4.

As can be seen by the dissolution data provided in Table 4, each ofExamples 16-19 provided a dissolution profile in which 50% of the drugis released in 8.5 to 10 hours. Once again, the dissolution rates arerelated to the ratio of drug to gums, with slight variances due to thechoice of inert diluent. The importance of the total weight of thetablet in affecting the drug/gums ratio is also shown.

                  TABLE 3                                                         ______________________________________                                        Propranolol Hydrochloride Tablets                                                                              Average                                                                Total  Particle                                                                             Ratio of                                              % Gums in Weight size   Drug/                                 Example                                                                              Diluent  Excipient of Tablet                                                                            (microns)                                                                            Gums                                  ______________________________________                                        16     Lactose  40%       350 mg 185    1:6.6                                 17     L/D      40%       350 mg 221    1:6.6                                 18     Dextrose 50%       225 mg 202    1:5                                   19     Sucrose  40%       200 mg 209    1:3.6                                 ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Propranolol Hydrochloride Tablets                                             Dissolution Data (Distilled Water)                                            Example  2 hr     4 hr   8 hr   T.sub.50                                                                             T.sub.90                               ______________________________________                                        16       11.35    19.55  37.55  10     15-15.5                                17       13.40    22.05  47.40   8.50  16                                     18       14.10    22.29  43.12   9-9.5 15-15.5                                19       18.40    27.67  45.88   9     15                                     ______________________________________                                    

FIG. 2 is a graphical representation of the dissolution curve obtainedwith Examples 16-19.

EXAMPLES 20-28 Hydrophilic Material

Slow release propranolol tablets are prepared according to theprocedures set forth in Examples 1 and 2 which illustrate variousaspects of the present invention, including the addition of additionalpolysaccharide gums to the xanthan/locust bean gum mixture, andvariances in the ratio of xanthan gum to locust bean gum. In Examples20-22, the relative percentages of xanthan gum to locust bean gum areabout 0/100, 25/75 and 75/25, respectively. In Examples 23 and 24, 50%of the hydrophilic matrix is propylene glycol alginate (PGA) and 50% isxanthan gum/locust bean gum in a 1 1 ratio. Examples 25 and 26 aresimilar to Example 23, except that the propylene glycol alginate isreplaced with hydroxypropylmethyl cellulose 15M and 100M, respectively(both grades commercially available from Dow Chemical). Example 27 isalso similar to Example 23, except that the propylene glycol alginate isreplaced with sodium alginate. In Example 28, the excipient includesonly xanthan gum. In each of Examples 20-28, the inert diluent isdextrose. To the excipient mixture, 20 mg propranolol hydrochloride isadded. The tablets produced in each of Examples 20-27 weigh 350 mg.

In Comparative Example C, the excipient is 30% hydroxypropylmethylcellulose and 70% dextrose by weight. The tablets of Comparative ExampleC also weighs 350 mg and includes 20 mg of propranolol hydrochloride.Table 5 sets forth the gums used in Examples 20-28 and ComparativeExample C.

The dissolution of the tablets of Examples 20-28 and Comparative ExampleC is then tested in distilled water in an automated USP dissolutionapparatus. The results are provided in Table 6.

                  TABLE 5                                                         ______________________________________                                        % Gums in Hydrophilic Material                                                                 Locust                                                                        Bean                  Na                                     Example                                                                              Xanthan   Gum      PGA   HPMC   Alginate                               ______________________________________                                        20     --        100      --    --     --                                     21     25        75       --    --     --                                     22     75        25       --    --     --                                     23     25        25       50%   --     --                                     24     25        25       50%   --     --                                     25     25        25       --    50%    --                                     26     25        25       --    50%    --                                     27     25        25       --    --     50%                                    28      100%     --       --    --     --                                     C      --        --       --    100%   --                                     ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Dissolution of Propranolol Hydrochloride                                      (350 mg tablets, 20 mg drug)                                                  Ex-  % Gums   Ratio of                                                        am-  in       Drug/                                                           ple  Excipient                                                                              Gums     2 hr 4 hr 8 hr T.sub.50                                                                            T.sub.90                          ______________________________________                                        20   30%      1:5      32.13                                                                              46.06                                                                              62.06                                                                              4.5-5 18+                               21   40%        1:6.5  22.54                                                                              30.71                                                                              45.96                                                                              8.5-9 16-16.5                           22   40%        1:6.5  12.9 22.75                                                                              50.05                                                                              8     12.5-13                           23   30%      1:5      23.35                                                                              39.05                                                                              75.70                                                                              5-5.5 9.5-10                            24   40%        1:6.5  20.12                                                                              32.79                                                                              64.17                                                                              6-6.5 11-11.5                           25   30%      1:5      37.54                                                                              50.04                                                                              65.00                                                                              4     15.5-16                           26   30%      1:5      32.71                                                                              41.79                                                                              54.88                                                                              6-6.5 18                                27   30%      1:5      25.12                                                                              44.38                                                                              100  4-4.5 6.5-7                             28   30%      1:5      17.38                                                                              31.00                                                                              59.88                                                                              6-6.5 11-11.5                           C    30%      1:5      52.25                                                                              74.85                                                                              94.85                                                                              1.5-2 7                                 ______________________________________                                    

FIG. 3 is a graphical representation of the dissolution curves providedby Example 18 (xanthan gum/locust bean gum in a 1:1 ratio), Example 20(100% locust bean gum), and Example 28 (100% xanthan gum). From thegraph, it may be seen that the T₅₀ for Example 28 was longer than thatfor Example 20. The T₉₀ for Example 28, however, was shorter than thatfor Example 20. This result may be due to the fact that xanthan gum wetsquicker than locust bean gum (thereby providing a quicker forming gel)but does not have as good gel strength as locust bean gum. Thecombination of xanthan gum/locust bean gum provides an excipient whichboth wets quickly and has a high gel strength. The T₅₀ provided byExample 18 is longer than either Example 20 or 28. The T₉₀ of Example 18also reflects the improved gel strength obtained by the combination ofthe gums over xanthan gum alone.

FIG. 4 is another graphical representation showing the dissolution curveof Example 18 as compared to Comparative Example C (gum ishydroxypropylmethyl cellulose). This graph shows the synergistic effectof the combination of xanthan gum/locust bean gum as compared to a priorart hydrophilic gel matrix forming agent. One possible explanation forthis phenomenon is that hydroxypropylmethyl cellulose does not wet asquickly nor form a gel matrix which is as strong as the gums used inExample 18, and therefore does not provide a sufficient slow releaseprofile.

EXAMPLES 29-31 pH of the Environment

Propranolol hydrochloride tablets are prepared according to theprocedures set forth in Examples 1 and 2. The tablets of Examples 29-31have a total weight of 350 mg, of which 20 mg is the drug. The excipientcomprises 40% gums (xanthan gum/locust bean gum in a 1:1 ratio) and 60%of an inert diluent (lactose). The drug/gums ratio is about 1:6.5.

In Example 29, the dissolution of the tablets was measured in an aqueoussolution having a pH of 6.8. In Example 30, the dissolution of thetablets was measured in distilled water (pH=7). In Example 31, thedissolution of the tablets was measured in an acidic solution having apH of 2.

The tablets of Examples 29-31 are then tested to determine theirdissolution rates in environments having varied pH's (distilled water,pH 2, pH 6.8). The results are shown in FIG. 5 which is a graphicalrepresentation of the percentage of dissolved drug over time.

As can be seen from FIG. 5, the dissolution times of the tablets in pH6.8 and pH 2 are fairly close, while the dissolution time in unbuffereddistilled water does not provide a similar profile. From the graphicalrepresentation, it may be concluded that the dissolution of themedicament (in this case propranolol) does not vary greatly in ionicsolutions, even when the pH varies greatly, due to the relativeinsensitivity to pH of the excipients of the present invention.

EXAMPLES 32-36 Gum/total Excipient

Slow release excipients are prepared according to procedures set forthin Example 1. The excipients of Examples 32-36 each include dextrose andxanthan gum/locust bean gum in a 1:1 ratio. The percentage of gums ascompared to the total weight of the excipient in Examples 32-36 are 30%,40%, 50%, 60% and 70%, respectively. The viscosities of the excipientsare then determined at four different RPM's using a #2 spindle on aBrookfield viscometer. The results are shown in FIG. 6. As can be seenfrom the graph, the viscosity increases as the percentage of gumincluded in the excipient increases.

EXAMPLE 37 Preparation of Excipient

A slow release excipient according to the present invention is preparedas follows. First, 630 g of dextrose and 270 g of a hydrophilic materialcomprising 135 g of Xanthan gum and 135 g of locust bean gum, all in apowder form having an average particle size of less than 50 microns areblended for two minutes in a granulator (i.e., a high speed mixer havinga combination chopper/impeller). After pre-mixing, 100 ml of water isadded until there is sharp rise in the power consumed (about 2-3minutes). The mixed product, which is now in the form of granules, isremoved from the granulator and dried in a convection air-oven for 24hours at a temperature of about 40° C.-60° C. The dried granulation isthen passed through a 20 mesh screen. The product is now ready to begranulated with an active, the result of which is suitable forcompression to form a slow release tablet.

EXAMPLE 38 Wet Granulation

Verapamil HCl is a relatively soluble active ingredient which has a doseof about 240 mg in a sustained release tablet form.

In Example 38, the active ingredient (Verapamil) is granulated with theslow release excipient as follows. The excipient of Example 37 385 g isfirst blended with 115 g Verapamil HCl for two minutes in a granulator.After premixing, about 90 ml of water is added until there is a sharprise in the power consumed by the granulator (about 2-3 minutes). Themixed product, which is now in the form of granules, is removed from thegranulator and dried in a convection air-oven for 24 hours at atemperature of about 40° C.-60° C. The dried granulation is then passedthrough a 20 mesh screen. The final composition of the mixture is about7.0% of the excipient of Example 37, and 23.0% Verapamil HCl.

The mixture is blended with hydrogenated vegetable oil for 5 minutes ina V-blender. Magnesium stearate is then added and the mixture is blendedfor an additional 5 minutes The final composition of the mixture isabout 75.0% of the excipient of Example 37, 22.5% Verapamil HCl, 2.00%hydrogenated vegetable oil, and 0.500% magnesium stearate, by weight.The mixture is then compressed on a Stokes RB-2 rotary tablet press withsixteen stations. The average weight of the tablets produced is about1067 mg and the crushing strength about 7-8 kgs. Each tablet containsabout 240.08 Verapamil, 800.25 mg excipient of Example 37, 21.34 mghydrogenated vegetable oil, and 5.34 mg magnesium stearate.

EXAMPLE 39 Dry granulation

The active ingredient is directly compressed with the slow releaseexcipient of Example 37 to form sustained release tablets havingapproximately the same composition as those of Example 38 as follows.300 g of the excipient of Example 37 is first blended with 90 gVerapamil HCl for 10 minutes in a V-blender. Hydrogenated vegetable oilis then added and the mixture is blended for 5 minutes. Magnesiumstearate is then added and the mixture is blended for an additional 5minutes. The final composition of the mixture is the same as in Example38 and is tableted.

EXAMPLE 40 Mixed granulation

The active ingredient is granulated with 50% of the slow releaseexcipient as follows. Half of the excipient of Example 37 is firstblended with Verapamil HCl for 2 minutes in a granulator. Next, about 75ml of water is added until there is a sharp rise in power consumed(usually 2-3 minutes). The mixed product, which is now in the form ofgranules, is removed from the granulator and dried in a convectionair-oven for 24 hours at a temperature of about 40° C.-60° C. The driedgranulation is then passed through a 20 mesh screen. The finalcomposition is about 62.5% of the excipient of Example 37 and about37.5% Verapamil HCl. The mixture is then blended with other half ofexcipient of Example 37 for 10 minutes in V-blender. Hydrogenatedvegetable oil is then added and blended 5 minutes, magnesium stearate isthen added and blended for an additional 5 minutes. The finalcomposition of the mixture is the same as in Example 38 and Example 39and is tableted.

EXAMPLES 41-43 Effect of Method of Incorporation

In Examples 41-43, the active ingredient (Verapamil HCl) is granulatedwith the slow release excipient according to the methods set forth inExamples 37-39 in order to compare the dissolution curves obtained.

In Example 41, the excipient is prepared according to the process setforth in Example 37 and is then blended with the active ingredient andtableted according to the process set forth in Example 38. In Example42, the excipient is prepared according to the process set forth inExample 37 and is then blended with the active ingredient and tableted,according to the process set forth in Example 39. In Example 43, theexcipient is prepared according to the process set forth in Example 37and is then blended with the active ingredient and tableted according tothe process set forth in Example 40.

In each of Examples 41-43, the tablets weigh about 1067 mg. The drug:gumratio in each of Examples 41-43 is 1 1; and the locust bean gum (LBG) toxanthan gum (XG) ratio is 1:1.

Each tablet of Examples 41-43 contain about 240 mg verapamil HCl, about800 mg excipient, about 21.3 mg hydrogenated vegetable oil, and about5.3 mg magnesium stearate. Further information regarding Examples 41-43is provided in Table 7 below.

                  TABLE 7                                                         ______________________________________                                               Drug:Gum   % Gum in  LBG:XG                                            Example                                                                              Ratio      Excipient Ratio   T50  T90                                  ______________________________________                                        41     1:1        35        1:1     3.7  16.5                                 42     1:1        35        1:1     1.0   4.5                                 43     1:1        35        1:1     2.4  --                                   ______________________________________                                    

The tablets are tested in an automated USP dissolution apparatus, usingdistilled water at a volume of 1 liter and paddle method at 50 R.P.M. At30 minute intervals the ultraviolet absorbance of filtered portions ofsolution are compared to a standard having a known concentration of USPVerapamil HCl in the same medium. The results are provided in FIG. 7.

EXAMPLES 44-46 Effect of Amount of Gum in Excipient

In Examples 44-46, the amount of gum in the excipient is varied in orderto compare the dissolution curves of the active ingredient (verapamilHCl) obtained.

In each of Examples 44-46, the slow release excipient is preparedaccording to the process set forth in Example 37, except that the amountof gum in the excipient is varied. The slow release excipient obtainedfor each of Examples 44-46 is then blended with the active ingredientand tabletted according to the method set forth in Example 40.

The tablets of Example 44 weigh about 861.5 mg and contain about 240 mgverapamil HCl, about 600 mg excipient, about 17.2 mg hydrogenatedvegetable oil, and about 4.3 mg magnesium stearate. The tablets ofExample 45 weigh about 949.70 mg and contain about 240 mg verapamil HCl,about 686 mg excipient, about 19 mg hydrogenated vegetable oil, andabout 4.70 mg magnesium stearate. The tablets of Example 46 weigh about1066.60 mg and contain about 240 mg verapamil HCl, about 800 mgexcipient, about 21.3 mg hydrogenated vegetable oil, and about 5.3 mgmagnesium stearate. Further information regarding Examples 44-46 isprovided in Table 8 below.

                  TABLE 8                                                         ______________________________________                                               Drug:Gum   % Gum in  LBG:XG                                            Example                                                                              Ratio      Excipient Ratio   T50  T90                                  ______________________________________                                        44     1:1        40        1:1     2.9  --                                   45     1:1        35        1:1     2.4  --                                   46     1:1        30        1:1     1.2  3.3                                  ______________________________________                                    

The tablets are then tested for dissolution in the same manner as inExamples 41-43. The results are provided in FIG. 8.

EXAMPLES 47-50 LBG:XG Ratio

In Examples 47-50, the ration of locust bean gum (LBG) to xanthan gum(XG) is varied and the dissolution curves compared.

In each of Examples 47-50, the slow release excipient is preparedaccording to the process set forth in Example 37, except that the LBG:XGratio is varied. The slow release excipient obtained for each ofExamples 47-50 is then blended with the active ingredient (verapamilHCl) and tabletted according to the process set forth in Example 40.

Each of the tablets of Examples 47-50 contain about 240 mg VerapamilHCl, about 738 mg excipient, about 20 mg hydrogenated vegetable oil, andabout 5 mg magnesium stearate. Further information regarding Examples47-50 is provided in Table 9 below.

                  TABLE 9                                                         ______________________________________                                               Drug:Gum   % Gum in  LBG:XG                                            Example                                                                              Ratio      Excipient Ratio   T50  T90                                  ______________________________________                                        47     1:1        32.5      55:45   0.9  5.0                                  48     1:1        32.5      60:40   0.3  0.5                                  49     1:1        32.5      1:1     2.7  11.5                                 50     1:1        32.5      25:75   4.8  17.5                                 ______________________________________                                    

The tablets are then tested for dissolution in the same manner as inExamples 41-43. The results are provided in FIG. 9.

EXAMPLES 51-53 Drug:Gum Ratio

In Examples 51-53, the drug to gum ratio is varied and the dissolutioncurves compared.

In each of Examples 51-53, the slow release excipient is preparedaccording to Example 37 and is then blended with the active ingredient(Verapamil HCl) and tableted.

In Example 51, the tablets contain about 240 mg Verapamil, about 240 mgexcipient, about 9.84 mg hydrogenated vegetable oil, and about 2.6 mgmagnesium stearate. In Example 52, the tablets contain about 240 mgVerapamil, about 480 mg excipient, about 14.8 mg hydrogenated vegetableoil, and about 3.7 mg magnesium stearate. In Example 53, the tabletscontain about 120 mg Verapamil, about 720 mg excipient, about 17.2 mghydrogenated vegetable oil, and about 4.3 mg magnesium stearate. Furtherinformation regarding Examples 51-53 is set forth in Table 10 below.

                  TABLE 10                                                        ______________________________________                                               Drug:Gum   % Gum in  LBG:XG                                            Example                                                                              Ratio      Excipient Ratio   T50  T90                                  ______________________________________                                        51     2:1        50        1:1     0.4  0.9                                  52     1:1        50        1:1     5.5  --                                   53     1:3        50        1:1     --   --                                   ______________________________________                                    

The tablets are then tested for dissolution in the same manner as inExamples 41-43. The results are provided in FIG. 10.

EXAMPLES 54-57 Tailoring to a Known Dissolution Curve

By varying the amount of gum, the LBG:XG ratio, the method ofincorporation, or the drug:gum ratio, it is possible to closely matchthe dissolution profile of a different slow release formulation of thesame drug. This is demonstrated in the following example.

First, a slow release excipient is prepared according to the process setforth in Example 37.

In Example 54, the excipient is then blended with the active ingredient(verapamil HCl) and tableted according to the process set forth inExample 38. Each tablet contains about 260 mg Verapamil, about 780 mgexcipient, about 21.3 mg hydrogenated vegetable oil, and about 5.3 mgmagnesium stearate. The tablets are then tested for dissolution in thesame manner as in Examples 41-43. As a comparative example, a Calan® SRcaplet (containing 240 mg Verapamil hydrochloride), available from G. D.Searle & Co., is similarly tested for dissolution. Further informationregarding Example 54 is provided in Table 11 below, and the dissolutioncurves for Example 54 and Calan® SR are provided in FIG. 11.

                  TABLE 11                                                        ______________________________________                                                Drug:Gum  % Gum in  LBG:XG                                            Example Ratio     Excipient Ratio   T50  T90                                  ______________________________________                                        18      1:0.9     50        1:1     2.4  5.9                                  Calan ®SR                                                                         --        --        --      2.3  4.5                                  ______________________________________                                    

In Example 55, the excipient is blended with propranolol and tabletedaccording to the process set forth in Example 38. Each tablet weighsabout 820.5 mg, and contains 160 mg propranolol HCl, 16.4 mghydrogenated vegetable oil, 4.10 mg magnesium stearate, and 640 mgexcipient (containing 50% gums (XG:LBG in a 1:1 ration). The tablets arethen tested for dissolution in the same manner as Examples 41-43 and thedissolution curve compared to a similarly tested tablet of Inderal® LA(a slow release formulation containing 160 mg propranolol HCl; availablefrom Wyeth-Ayerst. The results are proved in FIG. 12.

In Example 56, the excipient is blended with chlorpheniramine maleateand tableted according to the process set forth in Example 38. Eachtablet weighs about 100 mg, and contains about 12 mg chlorpheniraminemaleate, about 0.5 mg excipient, and about 87.5 mg excipient (containing50% gums (XG:LBG in a 1:1 ratio). The tablets are then tested fordissolution in the same manner as Examples 41-43, and the dissolutioncurves compared to a similarly tested tablet of Chlortrimeton® (a slowrelease formulation containing 12 mg chlorpheniramine maleate),available from Schering. The results are provided in FIG. 13.

In Example 57, the excipient is blended with phenylpropanolamineaccording to the process and tableted set forth in Example 38. Eachtablet weighs about 845 mg, and contains about 75 mgphenylpropanolamine, 16.9 hydrogenated vegetable oil, 4.2 mg magnesiumstearate, and 748.9 mg excipient (containing 50% gums (XG:LBG in a 1:1ration). The tablets are then tested for dissolution in the same manneras Examples 41-43, and the dissolution curve compared to a similarlytested tablet of Acutrim® (a slow release tablet containing 75 mgphenylpropanolamine), available from Ciba Consumer Products. The resultsare provided in FIG. 14. FIG. 15 is a graphical representation of thebioavailability of Example 57 as compared to Acutrim®. The results areobtained in a two-way crossover study on six healthy male subjects (12blood samples withdrawn and assayed for phenylpropanolamine in bloodplasma).

As can be seen from the results obtained in Examples 54-57, the slowrelease excipient of the present invention is extremely versatile andreadily provides formulations which can substantially match thedissolution curves of other slow release formulations.

The preceding theories are offered solely by way of explanation and itis not intended that the invention be limited to this theory.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

We claim:
 1. A controlled release pharmaceutical excipient for use inoral solid dosage forms, comprisingfrom about 20 to about 60 percent byweight of a hydrophilic material comprising xanthan gum and agalactomannan gum capable of cross-linking said xanthan gum in thepresence of aqueous solutions, the ratio of said xanthan gum to saidgalactomannan gum being from about 3:1 to about 1:3, and from about 40to about 80 percent by weight of an inert diluent selected from thegroup consisting of a monosaccharide, a disaccharide, a polyhydricalcohol, and mixtures thereof, the ratio of said inert diluent to saidhydrophilic material being from about 4:1 to about 0.67:1.
 2. Acontrolled-release tablet for absorption of an active medicament in thegastrointestinal tract, comprisinga controlled-released excipientcomprising a hydrophilic gum matrix comprising a xanthan gum and agalactomannan gum capable of cross-linking said xanthan gum when exposedto gastric fluid, the ratio of said xanthan gum to said galactomannangum being from about 3:1 to doubt 1:3, and an inert diluent, the ratioof said inert diluent to said hydrophilic gum matrix being from about4:1 to about 0.67:1, and an effective amount of a medicament to render atherapeutic effect, the ratio of said medicament to said hydrophilic gummatrix being from about 1:3 to about 1:10.
 3. The excipient of claim 1,wherein said galactomannan comprises locust bean gum.
 4. The excipientof claim 1, wherein said inert pharmaceutical filler comprises lactose,dextrose, sucrose, fructose, microcrystalline cellulose, xylitol,sorbitol or mixtures thereof.
 5. The excipient of claim 1 to which aneffective amount of a therapeutically active medicament is added.
 6. Theexcipient of claim 1, wherein an effective amount of a therapeuticallyactive medicament is added via dry granulation, yet granulation or acombination of dry and wet granulation and the resultant granulation iscompressed to form solid tablets.
 7. The excipient of claim 3, whereinsaid hydrophilic material further comprises one or more of tragacanth,acacia, karaya, alginates, agar, pectin, guar, hydroxypropyl guar,carrageenan, hydroxypropylmethyl cellulose, hydroxypropyl cellulose,methylcellulose, carboxymethyl cellulose, polyvinyl pyrollidone, andmixtures of any of the foregoing.
 8. The excipient of claim 3, whereinsaid hydrophilic material further comprises propylene glycol alginate.9. The excipient of claim 3, wherein said hydrophilic material furthercomprises a hydrocolloid, said hydrocolloid comprising up to about 50%by weight of said hydrophilic material.
 10. The excipient of claim 1,wherein an effective amount of a therapeutically active medicament isadded and the resulting mixture is encapsulated.
 11. The excipient of toclaim 1, wherein an effective amount of a therapeutically activeingredient is added and the resulting mixture provides a zero ordercontrolled release when provided as a solid dosage form.
 12. Theexcipient of claim 3, wherein said ratio of xanthan gum to locust beangum is about 1:1.
 13. A slow release pharmaceutical excipient, for usein solid oral dosage forms comprisinga hydrophilic gum matrix comprisingxanthan gum and locust bean gum in a ratio of about 3:1 to about 1:3;and an inert diluent, the ratio of said inert diluent to saidhydrophilic gum matrix being from about 2.3:1 to about 1:1.
 14. Thetablet of claim 2, wherein said galactomannan gum is locust bean gum.15. The tablet of claim 2, wherein said medicament is added to saidexcipient via dry granulation, wet granulation or a combination of dryand wet granulation.
 16. A controlled release tablet for oraladministration comprising(I) from about 20 to about 60 percent by weightof a hydrophilic material comprising from about 10 to about 90 percentof a heteropolysaccharide and from about 90 to about 10 percent of across-linking agent capable of cross-linking said heteropolysaccharide;and (II) up to about 80 percent of an inert pharmaceutical fillerselected from the group consisting of a monosaccharide, a disaccharide,a polyhydric alcohol, and mixtures thereof, the ratio of said inertpharmaceutical filler to said hydrophilic material being from about 4:1to about 0.67:1; and (III) an effective amount of a therapeuticallyactive medicament to render a therapeutic effect.
 17. The tablet ofclaim 16, wherein said heteropolysaccharide comprises xanthan gum andsaid cross-linking agent comprises a galactomannan.
 18. The tablet ofclaim 17, wherein at least 3.5 hours ar required for 50 percent of saidtherapeutically active medicament to be released when said tablet isexposed to gastric fluid.
 19. The tablet of claim 17, wherein saidtablet provides a zero order controlled release of said therapeuticallyactive medicament when said tablet is exposed to gastric fluid.
 20. Thetablet of claim 17, wherein said galactomannan comprises locust beangum, and the ratio of xanthan gum to locust bean gum is about 1:1. 21.The tablet of claim 17, wherein said inert pharmaceutical fillercomprises lactose, dextrose, sucrose, fructose, xylitol, sorbitol ormixtures thereof.
 22. The tablet of claim 17, wherein said hydrophilicmaterial further comprises a polysaccharide gum selected from the groupconsisting of tragacanth, acacia, karaya, alginates, agar, pectin,carrageenan, hydroxypropylmethyl cellulose, hydroxypropyl cellulose,methylcellulose, carboxymethyl cellulose, polyvinyl pyrollidone, andmixtures of any of the foregoing.
 23. The tablet of claim 22, whereinsaid hydrophillic material further comprises propylene glycol alginate.24. The tablet of claim 22, wherein said hydrophilic material furthercomprises a hydrocolloid.